Maternal Antibodies Elicited by Immunization With an O- Polysaccharide Glycoconjugate Vaccine Protect Infant Mice Against Lethal Salmonella Typhimurium Infection

Abstract

Non-typhoidal Salmonella (NTS) are a leading cause of pediatric invasive bacterial infections in sub-Saharan Africa with high associated case fatality rates in children under 5 years old. We have developed glycoconjugate vaccines consisting of the lipid A-removed surface polysaccharide of NTS, core and O-polysaccharide (COPS), and the flagellar monomer protein (FliC) from the homologous serovar as the carrier. We previously established that COPS:FliC was immunogenic and protective in mice immunized as adults or infants; however, the brief period of murine infancy precluded the evaluation of protection against invasive NTS (iNTS) disease in early life. In the present study, we used a mouse model of maternal immunization to investigate transmission of S. Typhimurium COPS:FliC-induced maternal antibodies and protection against lethal iNTS challenge in infant mice. We found that vaccinated dams developed high levels of COPS- and FliC-specific IgG, which were transferred to their offspring. Sera from both vaccinated mothers and their litters mediated complement-dependent bactericidal activity in-vitro. Passively immunized 2-week old infant mice born to vaccinated mothers were fully protected from challenge with an S. Typhimurium blood isolate from sub-Saharan Africa. The pre-clinical findings reported herein demonstrate that anti-COPS:FliC antibodies induced by vaccination are sufficient for protection of murine infants against experimental S. Typhimurium infection. By underscoring the protective role of antibody, our results suggest that maintaining an adequate titer of protective anti-Salmonella antibodies during early life, either through pediatric or maternal COPS:FliC vaccination, may reduce iNTS disease in young children in sub-Saharan Africa.

Pathogenic signature of invasive non-typhoidal Salmonella in Africa: implications for vaccine development

“…157 Additionally, the passive transfer of S. Typhimurium COPS:FliC-induced maternal antibodies to infant mice proved to confer to the offspring nearly complete protection against lethal challenge with the Malian isolate S. Typhimurium D65, thereby providing further preclinical evidence that this vaccine may protect against pediatric iNTS disease in sSA. 158 More recently, a trivalent formulation containing iNTS COPS:FliC and the licensed S. Typhi Vi antigen-based conjugate vaccine Typbar-TCV has shown high immunogenicity and efficacy. 159 Immunization of rabbits with the trivalent typhoid-iNTS conjugate formulation elicited high serum IgG titers against all three polysaccharide antigens.…”

“…Typhimurium D65, thereby providing further preclinical evidence that this vaccine may protect against pediatric iNTS disease in sSA. 158 …”

Wild-type and single-O-antigen repeat outer-membrane vesicles induce equivalent protection against homologous and heterologousSalmonellachallenge

“…Protection against re-infection with Gram-negative bacteria is associated with antibodies to the bacterial cell-surface and all licensed human vaccines contain cell-surface or secreted antigens. In the absence of a capsular polysaccharide, the immunodominant O-antigen polysaccharide sub-component of lipopolysaccharide (LPS) is a key target of antibodies that provide serovar-specific protection against infection, but limited cross-protection against serovars that express a different O-antigen 5,6,7,8,9,10,11,12,13,14 . An elegant example can be seen after infection and challenge with different Salmonella serovars and isogenic strains that differ in their LPS O-antigen expression 6 .…”

Multiple immunodominant O-epitopes co-expression in live attenuated Salmonella serovars induce cross-protective immune responses against S. Paratyphi A, S. Typhimurium and S. Enteritidis

“…However, multi-valent strategies are being explored in clinical development. For example, a bivalent outer membrane vesicle approach, also referred to as Generalized Modules for Membrane Antigens (GMMA) [19], targets S. Enteritidis and S. Typhimurium, and a trivalent glycoconjugate approach targets S. Enteritidis, S. Typhimurium, and S. Typhi [20,21]. Both of them involve in O-antigens formulation.…”